DESCRIPTION (provided by applicant: Despite scientific and programmatic advances, tuberculosis (TB) continues to be the leading cause of death in the world from a curable infection, making TB prevention a continuing health priority. Thus far, TB prevention has been limited by a lack of understanding of the transition from latent to active disease. To address this knowledge barrier, we propose to study how a modifiable risk factor, type-2 diabetes mellitus, affects risk of active TB. Epidemiological studies have shown a strong association between diabetes and TB, but have failed to provide enough information to translate those findings into clinical practice. The alarming increase in the global prevalence of diabetes portends intensified difficulties in TB control. Active TB in persons with diabetes could be prevented if the risks are better understood and screening programs are appropriately framed. We hypothesize that the severity of insulin resistance and metabolic derangement in type-2 diabetes are key determinants of active tuberculosis disease. The hypothesis will be addressed using two existing large cohorts in the Northern California Kaiser Permanente health maintenance organization, one of the oldest and most diverse subscriber populations in the U.S. These two cohorts-the Multiphasic Health Check-up (MHC, 206,974 individuals) and the Kaiser Permanente Diabetes Registry (DR, 372,477 individuals)-include at least 600, and potentially as many as 2000, incident cases of tuberculosis since enrollment over up to 40 years of follow-up. Clinical data already available will be combined with new laboratory testing on banked serum to address three aims: 1. We will establish the incidence of tuberculosis and describe the demographic risk factors for active TB in our cohorts. 2. We will dissect and characterize the association between tuberculosis and type 2 diabetes. We will evaluate how biochemical profiles (glycemia, dyslipidemia, insulin levels, and systemic inflammation) and co- morbidity profiles (duration of diabetes, body mass index, microalbuminuria, smoking, etc.) in insulin resistant diabetes affect risk of tuberculosis. 3. Finally, we will assess the epidemiology and efficacy of current TB screening and treatment practices in our population and evaluate if our findings from aims 1 and 2 can be used to improve current TB guidelines to increase capture of preventable TB cases. This will be the first, large, population-based cohort study with prospectively collected data to evaluate the association between diabetes and TB in the United States. It will also be the first to dissect the progression of insulin resistance and metabolic dysregulation on risk of active TB. The project builds upon the candidate's solid foundation of clinical and epidemiology expertise in infectious diseases and tuberculosis. The expert faculty advisors, support of the institution, and the candidate's proposed career development plan of didactic training and hypothesis-driven research will ensure successful transition to independence as a patient-oriented research investigator. The proposed work is an innovative, interdisciplinary, and a translational approach to clinically important questions. The findings will inform public health policy on the intersection of diabetes and TB and will, more generally, help frame future cost-effectiveness studies to decrease the burden of TB in the U.S. and in the world. PUBLIC HEALTH RELEVANCE (provided by applicant): Tuberculosis is the leading cause of death in the world from a curable infection. Studies have shown a strong association between diabetes and increased risk of tuberculosis, but have failed to provide enough information to put those findings into clinical practice. The project aims to characterize the metabolic changes and medical conditions associated with insulin resistance and diabetes that increase the risk of tuberculosis, and to evaluate how current screening and treatment guidelines can be changed to improve the prevention of tuberculosis in the U.S. and in the world.